NMDA receptors consist of NMDA receptor 1 (NR1) subunits and members of a family of glutamate-binding NR2 subunits (NR2A-D) (Ikeda K, et al. (1992) FEBS Lett 313:34-38; Monyer H, et al. (1992) Science 256:1217-1221; Ishii T, et al. (1993) J Biol Chem 268:2836-2843). Recombinant NMDA receptors that contain NR1 subunits and subunits NR2A or B require a strong depolarization to overcome Mg2+ blockade and have high conductances, whereas those with NR2C or D need only modest depolarization to overcome Mg2+ blockade and show low conductances (Monyer et al., id., and Monyer H, et al. (1994) Neuron 12:529-540). Native NMDA receptors containing NR2D are estimated to form ˜10% of the NMDA receptor population in the cortex of adult rats (Dunah A W, et al. (1998) Mol Pharmacol 53:429-437). Additionally, levels of expression of these subunits are higher in juvenile animals Dunah A W, et al. (1996) J Neurochem 67:2335-2345; Wenzel A, et al. (1996) J Neurochem 66:1240-1248), in which long-term depression can most efficiently be produced (Dudek S M, Bear M F (1993) J Neurosci 13:2910-2918.). CA1 pyramidal cells express mRNA for NR2A, 2B, and 2D in adult humans (Scherzer C R, et al. (1998) J Comp Neurol 390:75-90) and in juvenile rats (Kirson ED, et al. (1999) J Physiol (Lond) 521:99-111). Currents attributable to NMDA receptors containing NR2D subunits have also been observed in juvenile CA1 pyramidal cells (Kirson et al., id.).
NMDA receptor subpopulations containing these different subunits can be distinguished by competitive NMDA receptor antagonists with different affinities to the glutamate-binding site of the various NR2s (Monaghan D T, et al. (1998) Prog Brain Res 116:158-177).
In the hippocampal CA1 region and the cerebral cortex, both long-term potentiation (LTP) and long-term depression (LTD) can depend on the activation of NMDA receptors, because both can be blocked by the NMDA receptor antagonist D/L-2-amino-5- phosphonovaleric acid (D/L-AP5) (Collingridge G L, et al. (1983) J Physiol (Lond) 334:34-46; Harris E W, et al. (1984) Brain Res 323:132-137; Dudek S M, Bear M F (1992) Proc Natl Acad Sci USA 89:4363-4367; Mulkey R M, Malenka R C (1992) Neuron 9:967-975; Kirkwood A, et al. (1993) Science 260:1518-1521; Christie B R, et al. (1996) Learn Mem 3:160-169; Cummings J A, et al. (1996) Neuron 16:825-833). High-frequency stimulation causes strong activation of the ligand- and voltage-dependent NMDA receptors. A large influx of Ca2+ into postsynaptic neurons follows to trigger potentiation. Low-frequency stimulation results in moderate activation of NMDA receptors and a moderate influx of Ca2+, leading to depression. An additional mechanism participating in this bi-directional response, however, may be that high- and low-frequency stimulation activate distinct subpopulations of NMDA receptors (Hrabetova S, Sacktor T C (1997) Neurosci Lett 226:107-110).
Various amino acids have become of interest following the discovery that they are able to influence the binding and modulation of certain receptors in the central nervous system (CNS), including the NMDA receptor. Attention has been directed to the identification of novel compounds that selectively bind and activate or block these receptor sites. Such compounds may be used to advantage to treat disorders resulting from CNS malfunction including, for example, various involuntary muscular activity and/or mental and/or affective disorders.
A number of piperazine-2-carboxylic acid and piperazine-2,3-dicarboxylic acid analogues have been synthesised as potential NMDA receptor antagonists. EP-A-0159889 and GB-A-2157685 disclose several such compounds, including 1-(4-bromobenzoyl)-piperazine-2,3-dicarboxylic acid (BrBzPDA). The compounds are, however, relatively weak NMDA receptor antagonists and they are also relatively non-selective for the NMDA receptors, in that they also antagonize alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate-induced depolarizations on neonatal rat motoneurones.
A more potent and selective NMDA receptor antagonist, namely 1-(4-phenylbenzoyl)-piperazine-2,3-dicarboxylic acid, (PBPD), has been described by Buller et al., European Journal of Pharmacology, 320, (1997), 87-94. PBPD displays some NMDA receptor subtype selectivity. Indeed, PBPD displays the opposite selectivity to previously described antagonists such as 4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPP-ene) in that it selectively antagonises NR1/NR2B or NR1/NR2D receptors over those containing NR1/NR2A or NR1/NR2C. However, PBPD is only of moderate potency when compared to previously described antagonists such as CPP-ene.
There remains a need for NMDA receptor antagonists which have high potency and/or exhibit selectivity for particular NMDA receptor subtypes. It is an aim of the invention to provide such compounds